Osteoporos Int (2015) 26:85–91 DOI 10.1007/s00198-014-2939-3
ORIGINAL ARTICLE
Ankylosing spondylitis confers substantially increased risk of clinical spine fractures: a nationwide case-control study D. Prieto-Alhambra & J. Muñoz-Ortego & F. De Vries & D. Vosse & N. K. Arden & P. Bowness & C. Cooper & A. Diez-Perez & P. Vestergaard
Received: 15 May 2014 / Accepted: 14 October 2014 / Published online: 24 October 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Ankylosing spondylitis (AS) leads to osteopenia/ osteoporosis and spine rigidity. We conducted a case-control study and found that AS-affected patients have a 5-fold and 50 % increased risk of clinical spine and all clinical fractures, respectively. Excess risk of both is highest in the first years and warrants an early bone health assessment after diagnosis. Introduction Ankylosing spondylitis (AS) is related to spine rigidity and reduced bone mass, but data on its impact on fracture risk are scarce. We aimed to study the association between AS and clinical fractures using a case-control design. Methods From the Danish Health Registries, we identified all subjects who sustained a fracture in the year 2000 (cases) and matched up to three controls by year of birth, gender and region. Clinically diagnosed AS was identified using International Classification of Diseases, 8th revision (ICD-8; 71249), and International Classification of Diseases, 10th revision
(ICD-10; M45) codes. We also studied the impact of AS duration. Conditional logistic regression was used to estimate crude and adjusted odds ratios (ORs) for non-traumatic fractures (any site, clinical spine and non-vertebral) according to AS status and time since AS diagnosis. Multivariate models were adjusted for fracture history, socio-economic status, previous medical consultations, alcoholism and use of oral glucocorticoids. Results We identified 139/124,655 (0.11 %) AS fracture cases, compared to 271/373,962 (0.07 %) AS controls. Unadjusted (age- and gender-matched) odds ratio (OR) were 1.54 [95 % confidence interval (95 %CI) 1.26–1.89] for any fracture, 5.42 [2.50–11.70] for spine and 1.39 [1.12–1.73] for non-vertebral fracture. The risk peaked in the first 2.5 years following AS diagnosis: OR 2.69 [1.84–3.92] for any fracture. Conclusions Patients with AS have a 5-fold higher risk of clinical spine fracture and a 35 % increased risk of non-
D. Prieto-Alhambra : N. K. Arden : P. Bowness : C. Cooper Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
F. De Vries Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
D. Prieto-Alhambra : F. De Vries : N. K. Arden : C. Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
F. De Vries Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Utrecht, The Netherlands
D. Prieto-Alhambra : A. Diez-Perez URFOA-IMIM and RETICEF, Parc de Salut Mar and Instituto de Salud Carlos III, Barcelona, Spain
D. Vosse Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, The Netherlands
D. Prieto-Alhambra GREMPAL Research Group, IDIAP Jordi Gol Primary Care Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain J. Muñoz-Ortego Rheumatology Department, Hospital Universitari Sagrat Cor, Barcelona, Spain
P. Vestergaard Aalborg University Hospital, Aalborg University, Aalborg, Denmark P. Vestergaard (*) Department of Endocrinology, Aalborg Hospital, Medicinerhuset Mølleparkvej 4, 9000 Aalborg, Denmark e-mail: [email protected]
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vertebral fracture. This excess risk peaks early, in the first 2.5 years of AS disease. Patients should be assessed for fracture risk early after AS diagnosis.
Methods
Keywords Ankylosing . Bone . Electronic health records . Epidemiology . Fractures . Spondylitis
The extensive nature of registers in Denmark covering contacts to the health sector offers good possibilities for studies on the occurrence of fractures [22]. Using the unique 10-digit civil registry number that is assigned to all Danish citizens shortly after birth, a complete hospital discharge and prescription history can be established for each individual, and valid linkage between population-based registries can be obtained. The unique civil registry number is used in all registers, i.e. if a person buys a drug on prescription, the drug is registered as bought by this individual, and the same applies for admissions to hospitals and contacts to general practitioners for reimbursement purposes. This case-control study was performed within the Danish population that constituted approximately 5.3 million individuals during the study period. The study was subject to control by the National Board of Health and the Danish Data Protection Agency.
Introduction Ankylosing spondylitis (AS) is one of the most common inflammatory arthritides, with a prevalence of 0.1 to 1.4 % in Caucasian populations [1, 2]. Unlike rheumatoid arthritis, which affects preferentially peripheral joints, AS is characterized by inflammation of the spinal joints. This has two consequences with a potential impact on vertebral fracture risk: firstly, inflammationmediated reduction in bone mineral density [3] and secondly, a progressive bone formation and ankylosis leading, if no effective treatment is provided, to “bamboo spine” [4]. Such a risk is important to quantify, as spine fractures can have devastating consequences for these patients, including neurological sequelae [5, 6] and intra-abdominal injuries, which are more common in AS patients who suffer transversal fractures of the vertebral body (Chance fracture) [7]. In a previous study, we characterized 66 patients with AS who sustained clinical vertebral fractures, mainly after minor trauma [8]: 47 % of these patients reported neurological complications. However, data on the impact of AS on fracture risk is scarce, and fracture prevalence varies greatly in the literature, from as low as 0.4 % to as high as 32 % [9–13]. This large difference reflects in part the problems of recognition of vertebral fractures in patients with AS: back pain is often misinterpreted as a flare of disease and fractures can be missed on plain radiographs [14]. Previous studies have shown that bone resorption biomarkers are up-regulated in AS patients compared with healthy controls and may correlate with inflammatory activity [15, 16]. Loss of bone mass in both hips and vertebrae due to inflammation are well recognized in patients with severe and long-term AS [17]. Even more worrying, recent findings suggest that even patients with early AS have a low bone mineral density (BMD) and a high prevalence of spine fractures [18, 19]. In a recently reported retrospective cohort study by our group, we have reported an increased risk of clinical vertebral and non-vertebral fractures among patients with AS [20, 21]. The aim of the current study was to analyse the association between AS and the risk of non-traumatic fractures (all, clinical spine and non-vertebral) in a case-control study using data from the Danish Health Registries.
Data source
Study design This study was designed as a classical case-control study. Cases were all subjects, both genders and all ages, who sustained a fracture during the year 2000. Controls were matched subjects without a fracture in the same year using the criteria below. Exposure was use of drugs and diseases before the date of fracture or a matched index date in the controls. Information on fractures and diseases prior to the fracture was based on hospital records of in- and outpatients. Identification of fracture cases In Denmark, the National Hospital Discharge Register covers all contacts (on in- or outpatient basis) to the hospitals [23, 24]. The register was founded in 1977, but outpatient records were first completely incorporated from 1995. The files of the National Hospital Discharge Register include information on the civil registry number of the patient, date of discharge and discharge diagnoses, assigned exclusively by the physician at discharge according to the Danish version of the International Classification of Diseases, 8th revision (ICD-8), until the end of 1993, and to the Danish version of the International Classification of Diseases, 10th revision (ICD-10). The register has nationwide coverage of public hospitals with an almost 100 % completeness of recordings and a high precision of diagnoses [23, 24], particularly for fracture diagnoses [25]. Using the National Hospital Discharge Register, we identified all subjects who had sustained a clinically apparent fracture between 1 January 2000 and 31 December 2000 (n=124,655). Clinical spine fractures were the primary outcome of interest.
Osteoporos Int (2015) 26:85–91
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Data on ankylosing spondylitis
analysis, we also adjusted the association for use of bisphosphonates and hormone replacement therapy (HRT). We further stratified the analyses by NSAID use, as previous studies have shown a discordant effect of AS on fracture risk according to NSAID utilization [12, 20, 21]. Finally, we studied the association between the duration of AS and any clinical fracture by categorizing time since AS clinical diagnosis in quartiles (up to 2.5, >2.5 to 5, >5 to 12.5 and >12.5 years) for the analyses of all fractures and in tertiles (up to 1, >1 to 10 and >10 years) for the analyses of clinical spine fractures. We plotted a smooth spline representation of this association. All these analyses were performed using Stata 12.0 (StataCorp., College Station, TX) and SPSS 19.0 (SPSS Inc., Chicago Ill.). SPSS was used to generate the datasets from raw data and check the completeness of data, while Stata was used for the actual statistical analyses.
Patients with a diagnosis of 71249 (ICD-8) or M45.X (ICD10) were identified from the National Hospital Discharge Register.
Results
Any non-traumatic clinical fracture (any fracture not presenting with an accident mechanism code signalling a trauma of more than a fall at the same level or less as fracture energy) and non-vertebral clinical fractures were defined as secondary outcomes for this study. Selection of population-based controls Using the Civil Registration System, which has electronic records on all changes in vital status, including change of address and date of death for the entire Danish population since 1968, we randomly selected up to three controls for each case, matched by gender, year of birth and region. The controls were selected using the incidence-density sampling technique [26].
Data on baseline characteristics and potential confounders Using the National Hospital Discharge Register [23], we gathered information on the number of days spent in hospital the year preceding fracture (year 1999) and history of a prior fracture in the period 1977–2000. Similarly, data from the National Bureau of Statistics was obtained for a more accurate patient characterization including income, social status, working status and educational status in 1999. The National Health Organisation Register information was then used to study number of contacts to general practitioners and practising specialists for the period 1996 to 2000. Information on alcoholism was collected as appearance of a diagnosis of alcoholism in the National Hospital Discharge Register [23] or in the Psychiatric Central Register [27], or a prescription of disulfiram in the Prescription database. Statistics Data from the different registers were merged at the National Bureau of Statistics, and for each subject, the 10-digit civil registry number was substituted by a unique anonymous ID. The analyses of the association between AS and fractures (clinical spine, any non-traumatic and non-vertebral) in the year 2000 (cases vs. controls) were carried out using crude and multivariable conditional logistic regression models. The latter were adjusted for fracture history, annual income, social status, working status, educational status (in the year 1999), number of consultations to general practitioners and practising specialists (in 1996–2000), alcoholism (as defined above) and use of oral NSAIDs and oral corticosteroids. In a sensitivity
Baseline characteristics for fracture cases and controls are shown in Table 1. Cases had lower annual income, were more likely to be alcoholic and to have a history of previous fracture, had more comorbidities (Charlson index), and used more drugs with a negative effect on bone metabolism and fracture risk (corticosteroids, antiepileptics, sedatives, etc.). Among 124,655 cases, 139 (0.11 %) had a diagnosis of AS, while 271 (0.07 %) out of 373,962 controls had AS (crude odds ratio (OR) 1.54 [95 % confidence interval (95 %CI) 1.26–1.89]). Similarly, 18 (0.54 %) out of 3364 spine fracture cases compared to 10 (0.10 %) out of 10,079 matched controls had AS (age- and gender-matched OR 5.42 [2.50–11.70]). Finally, 121 (0.10 %) and 261 (0.07 %) AS participants were also identified among the 121,291 non-vertebral fracture cases and their corresponding 363,883 matched controls. In this group, the age- and gender-matched OR was 1.39 [1.12– 1.73]. The observed associations were attenuated after multivariable adjustment, with the exception of clinical spine fractures: adjusted OR 4.21 [1.78–9.96] [Table 2]. None of the observed associations changed after further adjustment for use of bisphosphonates/HRT (data not shown). The association between AS and any clinical fracture risk varied with AS disease duration: the excess risk was highest in patients with short-term AS of ≤2.5 years (age- and gender-matched OR 2.69 [1.84–3.92]), followed by those with a long-term disease >12.5 years (ageand gender-matched OR 1.48 [1.00–2.20]). No significant increase in any clinical fracture risk was seen for patients with >2.5 to ≤12.5 years since AS diagnosis. Figure 1 shows a smooth spline representation of this association that confirms this trend. Similarly, the
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Osteoporos Int (2015) 26:85–91
Table 1 Characteristics of fracture patients (cases—any fracture) and controls Variable
Cases (n=124,655)
Controls (n=373,962)
p
Age (years) Gender Men Women Annual income (DKR) Marital status Widowed Divorced Married Unmarried Othera Occupational status Independent Assisting wife Working Retired Otherb
43.44±27.39 (0–100)
43.44±27.39 (0–100)
– –
60,107 (48.2 %) 64,548 (51.8 %) 161,036±138,789
180,321 (48.2 %) 193,641 (51.8 %) 172,322±193,704
18,365 (14.8 %) 10,423 (8.4 %) 35,859 (28.9 %) 59,335 (47.8 %) 90 (0.1 %)
52,550 (14.2 %) 23,239 (6.3 %) 123,719 (33.3 %) 171,349 (46.2 %) 264 (0.1 %)
3374 (3.3 %) 209 (0.2 %) 37,797 (36.9 %) 40,201 (39.3 %) 20,752 (20.3 %)
11,816 (3.9 %) 951 (0.3 %) 124,984 (40.8 %) 109,447 (35.7 %) 59,278 (19.3 %)
Charlson indexc 0 1–2 3–4 ≥5 Previous fracture Alcoholism Ever use of any corticosteroid Ever use of NSAIDS Ever diagnosed with ankylosing spondylitis
97,256 (78.0 %) 19,634 (16.8 %) 5450 (4.4 %) 2315 (1.9 %) 41,315 (33.1 %) 8863 (7.1 %) 67,695 (54.3 %) 59,690 (47.9 %) 139 (0.1 %)
314,099 (84.0 %) 47,745 (12.8 %) 9132 (2.4 %) 2986 (0.8 %) 56,200 (15.0 %) 9473 (2.5 %) 189,636 (50.7 %) 142,274 (38.0 %) 271 (0.07 %)
ORIGINAL ARTICLE
Ankylosing spondylitis confers substantially increased risk of clinical spine fractures: a nationwide case-control study D. Prieto-Alhambra & J. Muñoz-Ortego & F. De Vries & D. Vosse & N. K. Arden & P. Bowness & C. Cooper & A. Diez-Perez & P. Vestergaard
Received: 15 May 2014 / Accepted: 14 October 2014 / Published online: 24 October 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Ankylosing spondylitis (AS) leads to osteopenia/ osteoporosis and spine rigidity. We conducted a case-control study and found that AS-affected patients have a 5-fold and 50 % increased risk of clinical spine and all clinical fractures, respectively. Excess risk of both is highest in the first years and warrants an early bone health assessment after diagnosis. Introduction Ankylosing spondylitis (AS) is related to spine rigidity and reduced bone mass, but data on its impact on fracture risk are scarce. We aimed to study the association between AS and clinical fractures using a case-control design. Methods From the Danish Health Registries, we identified all subjects who sustained a fracture in the year 2000 (cases) and matched up to three controls by year of birth, gender and region. Clinically diagnosed AS was identified using International Classification of Diseases, 8th revision (ICD-8; 71249), and International Classification of Diseases, 10th revision
(ICD-10; M45) codes. We also studied the impact of AS duration. Conditional logistic regression was used to estimate crude and adjusted odds ratios (ORs) for non-traumatic fractures (any site, clinical spine and non-vertebral) according to AS status and time since AS diagnosis. Multivariate models were adjusted for fracture history, socio-economic status, previous medical consultations, alcoholism and use of oral glucocorticoids. Results We identified 139/124,655 (0.11 %) AS fracture cases, compared to 271/373,962 (0.07 %) AS controls. Unadjusted (age- and gender-matched) odds ratio (OR) were 1.54 [95 % confidence interval (95 %CI) 1.26–1.89] for any fracture, 5.42 [2.50–11.70] for spine and 1.39 [1.12–1.73] for non-vertebral fracture. The risk peaked in the first 2.5 years following AS diagnosis: OR 2.69 [1.84–3.92] for any fracture. Conclusions Patients with AS have a 5-fold higher risk of clinical spine fracture and a 35 % increased risk of non-
D. Prieto-Alhambra : N. K. Arden : P. Bowness : C. Cooper Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
F. De Vries Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
D. Prieto-Alhambra : F. De Vries : N. K. Arden : C. Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
F. De Vries Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Utrecht, The Netherlands
D. Prieto-Alhambra : A. Diez-Perez URFOA-IMIM and RETICEF, Parc de Salut Mar and Instituto de Salud Carlos III, Barcelona, Spain
D. Vosse Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, The Netherlands
D. Prieto-Alhambra GREMPAL Research Group, IDIAP Jordi Gol Primary Care Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain J. Muñoz-Ortego Rheumatology Department, Hospital Universitari Sagrat Cor, Barcelona, Spain
P. Vestergaard Aalborg University Hospital, Aalborg University, Aalborg, Denmark P. Vestergaard (*) Department of Endocrinology, Aalborg Hospital, Medicinerhuset Mølleparkvej 4, 9000 Aalborg, Denmark e-mail: [email protected]
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Osteoporos Int (2015) 26:85–91
vertebral fracture. This excess risk peaks early, in the first 2.5 years of AS disease. Patients should be assessed for fracture risk early after AS diagnosis.
Methods
Keywords Ankylosing . Bone . Electronic health records . Epidemiology . Fractures . Spondylitis
The extensive nature of registers in Denmark covering contacts to the health sector offers good possibilities for studies on the occurrence of fractures [22]. Using the unique 10-digit civil registry number that is assigned to all Danish citizens shortly after birth, a complete hospital discharge and prescription history can be established for each individual, and valid linkage between population-based registries can be obtained. The unique civil registry number is used in all registers, i.e. if a person buys a drug on prescription, the drug is registered as bought by this individual, and the same applies for admissions to hospitals and contacts to general practitioners for reimbursement purposes. This case-control study was performed within the Danish population that constituted approximately 5.3 million individuals during the study period. The study was subject to control by the National Board of Health and the Danish Data Protection Agency.
Introduction Ankylosing spondylitis (AS) is one of the most common inflammatory arthritides, with a prevalence of 0.1 to 1.4 % in Caucasian populations [1, 2]. Unlike rheumatoid arthritis, which affects preferentially peripheral joints, AS is characterized by inflammation of the spinal joints. This has two consequences with a potential impact on vertebral fracture risk: firstly, inflammationmediated reduction in bone mineral density [3] and secondly, a progressive bone formation and ankylosis leading, if no effective treatment is provided, to “bamboo spine” [4]. Such a risk is important to quantify, as spine fractures can have devastating consequences for these patients, including neurological sequelae [5, 6] and intra-abdominal injuries, which are more common in AS patients who suffer transversal fractures of the vertebral body (Chance fracture) [7]. In a previous study, we characterized 66 patients with AS who sustained clinical vertebral fractures, mainly after minor trauma [8]: 47 % of these patients reported neurological complications. However, data on the impact of AS on fracture risk is scarce, and fracture prevalence varies greatly in the literature, from as low as 0.4 % to as high as 32 % [9–13]. This large difference reflects in part the problems of recognition of vertebral fractures in patients with AS: back pain is often misinterpreted as a flare of disease and fractures can be missed on plain radiographs [14]. Previous studies have shown that bone resorption biomarkers are up-regulated in AS patients compared with healthy controls and may correlate with inflammatory activity [15, 16]. Loss of bone mass in both hips and vertebrae due to inflammation are well recognized in patients with severe and long-term AS [17]. Even more worrying, recent findings suggest that even patients with early AS have a low bone mineral density (BMD) and a high prevalence of spine fractures [18, 19]. In a recently reported retrospective cohort study by our group, we have reported an increased risk of clinical vertebral and non-vertebral fractures among patients with AS [20, 21]. The aim of the current study was to analyse the association between AS and the risk of non-traumatic fractures (all, clinical spine and non-vertebral) in a case-control study using data from the Danish Health Registries.
Data source
Study design This study was designed as a classical case-control study. Cases were all subjects, both genders and all ages, who sustained a fracture during the year 2000. Controls were matched subjects without a fracture in the same year using the criteria below. Exposure was use of drugs and diseases before the date of fracture or a matched index date in the controls. Information on fractures and diseases prior to the fracture was based on hospital records of in- and outpatients. Identification of fracture cases In Denmark, the National Hospital Discharge Register covers all contacts (on in- or outpatient basis) to the hospitals [23, 24]. The register was founded in 1977, but outpatient records were first completely incorporated from 1995. The files of the National Hospital Discharge Register include information on the civil registry number of the patient, date of discharge and discharge diagnoses, assigned exclusively by the physician at discharge according to the Danish version of the International Classification of Diseases, 8th revision (ICD-8), until the end of 1993, and to the Danish version of the International Classification of Diseases, 10th revision (ICD-10). The register has nationwide coverage of public hospitals with an almost 100 % completeness of recordings and a high precision of diagnoses [23, 24], particularly for fracture diagnoses [25]. Using the National Hospital Discharge Register, we identified all subjects who had sustained a clinically apparent fracture between 1 January 2000 and 31 December 2000 (n=124,655). Clinical spine fractures were the primary outcome of interest.
Osteoporos Int (2015) 26:85–91
87
Data on ankylosing spondylitis
analysis, we also adjusted the association for use of bisphosphonates and hormone replacement therapy (HRT). We further stratified the analyses by NSAID use, as previous studies have shown a discordant effect of AS on fracture risk according to NSAID utilization [12, 20, 21]. Finally, we studied the association between the duration of AS and any clinical fracture by categorizing time since AS clinical diagnosis in quartiles (up to 2.5, >2.5 to 5, >5 to 12.5 and >12.5 years) for the analyses of all fractures and in tertiles (up to 1, >1 to 10 and >10 years) for the analyses of clinical spine fractures. We plotted a smooth spline representation of this association. All these analyses were performed using Stata 12.0 (StataCorp., College Station, TX) and SPSS 19.0 (SPSS Inc., Chicago Ill.). SPSS was used to generate the datasets from raw data and check the completeness of data, while Stata was used for the actual statistical analyses.
Patients with a diagnosis of 71249 (ICD-8) or M45.X (ICD10) were identified from the National Hospital Discharge Register.
Results
Any non-traumatic clinical fracture (any fracture not presenting with an accident mechanism code signalling a trauma of more than a fall at the same level or less as fracture energy) and non-vertebral clinical fractures were defined as secondary outcomes for this study. Selection of population-based controls Using the Civil Registration System, which has electronic records on all changes in vital status, including change of address and date of death for the entire Danish population since 1968, we randomly selected up to three controls for each case, matched by gender, year of birth and region. The controls were selected using the incidence-density sampling technique [26].
Data on baseline characteristics and potential confounders Using the National Hospital Discharge Register [23], we gathered information on the number of days spent in hospital the year preceding fracture (year 1999) and history of a prior fracture in the period 1977–2000. Similarly, data from the National Bureau of Statistics was obtained for a more accurate patient characterization including income, social status, working status and educational status in 1999. The National Health Organisation Register information was then used to study number of contacts to general practitioners and practising specialists for the period 1996 to 2000. Information on alcoholism was collected as appearance of a diagnosis of alcoholism in the National Hospital Discharge Register [23] or in the Psychiatric Central Register [27], or a prescription of disulfiram in the Prescription database. Statistics Data from the different registers were merged at the National Bureau of Statistics, and for each subject, the 10-digit civil registry number was substituted by a unique anonymous ID. The analyses of the association between AS and fractures (clinical spine, any non-traumatic and non-vertebral) in the year 2000 (cases vs. controls) were carried out using crude and multivariable conditional logistic regression models. The latter were adjusted for fracture history, annual income, social status, working status, educational status (in the year 1999), number of consultations to general practitioners and practising specialists (in 1996–2000), alcoholism (as defined above) and use of oral NSAIDs and oral corticosteroids. In a sensitivity
Baseline characteristics for fracture cases and controls are shown in Table 1. Cases had lower annual income, were more likely to be alcoholic and to have a history of previous fracture, had more comorbidities (Charlson index), and used more drugs with a negative effect on bone metabolism and fracture risk (corticosteroids, antiepileptics, sedatives, etc.). Among 124,655 cases, 139 (0.11 %) had a diagnosis of AS, while 271 (0.07 %) out of 373,962 controls had AS (crude odds ratio (OR) 1.54 [95 % confidence interval (95 %CI) 1.26–1.89]). Similarly, 18 (0.54 %) out of 3364 spine fracture cases compared to 10 (0.10 %) out of 10,079 matched controls had AS (age- and gender-matched OR 5.42 [2.50–11.70]). Finally, 121 (0.10 %) and 261 (0.07 %) AS participants were also identified among the 121,291 non-vertebral fracture cases and their corresponding 363,883 matched controls. In this group, the age- and gender-matched OR was 1.39 [1.12– 1.73]. The observed associations were attenuated after multivariable adjustment, with the exception of clinical spine fractures: adjusted OR 4.21 [1.78–9.96] [Table 2]. None of the observed associations changed after further adjustment for use of bisphosphonates/HRT (data not shown). The association between AS and any clinical fracture risk varied with AS disease duration: the excess risk was highest in patients with short-term AS of ≤2.5 years (age- and gender-matched OR 2.69 [1.84–3.92]), followed by those with a long-term disease >12.5 years (ageand gender-matched OR 1.48 [1.00–2.20]). No significant increase in any clinical fracture risk was seen for patients with >2.5 to ≤12.5 years since AS diagnosis. Figure 1 shows a smooth spline representation of this association that confirms this trend. Similarly, the
88
Osteoporos Int (2015) 26:85–91
Table 1 Characteristics of fracture patients (cases—any fracture) and controls Variable
Cases (n=124,655)
Controls (n=373,962)
p
Age (years) Gender Men Women Annual income (DKR) Marital status Widowed Divorced Married Unmarried Othera Occupational status Independent Assisting wife Working Retired Otherb
43.44±27.39 (0–100)
43.44±27.39 (0–100)
– –
60,107 (48.2 %) 64,548 (51.8 %) 161,036±138,789
180,321 (48.2 %) 193,641 (51.8 %) 172,322±193,704
18,365 (14.8 %) 10,423 (8.4 %) 35,859 (28.9 %) 59,335 (47.8 %) 90 (0.1 %)
52,550 (14.2 %) 23,239 (6.3 %) 123,719 (33.3 %) 171,349 (46.2 %) 264 (0.1 %)
3374 (3.3 %) 209 (0.2 %) 37,797 (36.9 %) 40,201 (39.3 %) 20,752 (20.3 %)
11,816 (3.9 %) 951 (0.3 %) 124,984 (40.8 %) 109,447 (35.7 %) 59,278 (19.3 %)
Charlson indexc 0 1–2 3–4 ≥5 Previous fracture Alcoholism Ever use of any corticosteroid Ever use of NSAIDS Ever diagnosed with ankylosing spondylitis
97,256 (78.0 %) 19,634 (16.8 %) 5450 (4.4 %) 2315 (1.9 %) 41,315 (33.1 %) 8863 (7.1 %) 67,695 (54.3 %) 59,690 (47.9 %) 139 (0.1 %)
314,099 (84.0 %) 47,745 (12.8 %) 9132 (2.4 %) 2986 (0.8 %) 56,200 (15.0 %) 9473 (2.5 %) 189,636 (50.7 %) 142,274 (38.0 %) 271 (0.07 %)
